Current cancer chemotherapy or radiation treatment is designed to kill all rapidly growing cells; thus, resulting in a very high incidence of adverse side effects and toxicity. Further, very few cancer treatments are specifically designed to prevent the metastatic development and progression of cancer. Keratinocyte growth receptor factor-tyrosine specific kinase (KGRF TK) inhibitors would be much less cytotoxic and specifically inhibit a critical step in the metastatic development of cancer cells which is responsible for most of the morbidity and mortality associated with cancer. The KGRF TK antagonists should be highly specific for KGF inhibition and should provide a high level of specificity, efficacy and safety in the treatment and/or prevention of cancer progression and metastasis.
Keratinocyte Growth Factor (KGF) is a member of the fibroblast growth factor family (also designated FGF-7) that is produced in stromal breast tissue and stimulates DNA synthesis, proliferation and migration of epithelial cells in the breast and other tissue (1-3). It is well established that these target epithelial cells contain high affinity KGF receptors (KGFR) (4, 5). In situ hybridization studies confirmed the specific mesenchymal production of KGF and epithelial localization of the KGFR in mammary tissue which provides further evidence that KGF is a mesenchymally-derived mediator of epithelial cell proliferation and migration (6, 7)
The mammary glands of adult female animals are remarkably sensitive to KGF (8). Systemic administration of KGF in adult male and female rats for 3 to 5 days was found to produce massive mammary ductal hyperplasia and an elevation of mitotic figures (8). Accordingly, intraductal hyperplasia is well known to be characteristic of premalignant breast lesions which leads to neoplasia. Similarly, Kitsberg and Leder (9) observed that female mice, with a constitutively up-regulated KGF transgene, develop mammary epithelial hyperplasia and eventually all animals developed metastatic mammary carcinomas. Consistent with this concept, KGFR gene up-regulation was observed in human primary breast tumor specimens (10). However, it was also observed that highly malignant, metastatic breast cancer tissue expressed relatively little KGFR (11). We recently reported that KGF treatment induced an up-regulation of the KGFR gene in ER-positive cells (12). This suggests that KGF-mediated stimulation of breast epithelial proliferation and migration may be an early event in the molecular cascade, which leads to breast cancer progression and metastasis (13). Thus, KGF would be expected to effectively stimulate well differentiated breast cancer cells (e.g. ER-positive breast cancer) and have little or no effect on less differentiated, highly malignant, tumor cells that have escaped normal regulatory mechanisms.
KGF binds to KGFR (also known as FGFR2 IIIb) found in epithelial cells, which is a splice variant of FGFR-2 encoded by the FGFR-2 gene (14). KGFR is a member of the fibroblast growth factor receptor (FGFR) family which are membrane-spanning tyrosine kinase receptors consisting of four known peptides whose sequences are highly conserved (15). It has been shown that there is a transition in the KGFR from the IIIb isoform in primary tumors, which is KGF-responsive, to the IIIIc isoform in advanced prostate cancer, which is unresponsive to KGF (16). If this KGFR transition occurs in breast cancer it would also support the concept that KGF is an early signal that is involved in the initiation of the cell migration and progression to aggressive growth and metastasis. Thus, KGF inhibition would provide and opportunity to inhibit breast tumor progression to a malignant phenotype.
Deregulation of receptor tyrosine kinase (TK) activity and the related signal transduction pathways is known to be involved in the development and metastatic progression of breast and other cancers (17). For example, it is well established that over-expression of the EGF receptor is predictive of aggressive and metastatic tumors in breast and other cancers (18, 19). Accordingly, specific TK inhibitors of the EGFR have been found to be effective therapeutically in the treatment of breast and other tumors (20, 21). Since we and other have demonstrated that KGF enhances breast cancer cell migration and tumor progression, we hypothesize that highly specific and potent KGFR TK inhibitors have a significant potential to be highly effective therapeutic agents in the treatment or prevention of breast cancer metastatic progression.